All publications mentioned throughout this application are fully incorporated herein by reference, including all references cited therein.
Tissue-specific proteins and their expression levels can be excellent indicators for the organism's health state as well as potential targets for treatment in case of disease.
Diseases which affect human beings may be categorized according to the mechanism of their cause. For example, diseases that have an immunological component or etiology include infectious diseases, acute and chronic inflammatory diseases, cancer, transplantation and autoimmune diseases.
The term inflammatory bowel disease (IBD) covers a group of disorders in which the intestines become inflamed (red and swollen), probably as a result of an immune reaction of the body against its own intestinal tissue, and therefore it is considered an auto-immune disorder.
Two major types of IBD have been described: ulcerative colitis (UC) and Crohn's disease (CD). As the name suggests, ulcerative colitis is limited to the colon (large intestine). Although Crohn's disease can involve any part of the gastrointestinal tract from the mouth to the anus, it most commonly affects the small intestine and/or the colon.
When there is severe inflammation, the disease is considered to be in an active stage, and the person experiences a flare-up of the condition. When the degree of inflammation is less (or absent), the person usually is without symptoms, and the disease is considered to be in remission.
The causes of inflammatory bowel disease are not fully clear. An unknown factor/agent (or a combination of factors) triggers the body's immune system to produce an inflammatory reaction in the intestinal tract that continues without control. As a result of the inflammatory reaction, the intestinal wall is damaged leading to bloody diarrhea and abdominal pain.
Genetic, infectious, immunologic, and psychological factors have all been implicated in influencing the development of IBD. There is a genetic predisposition (or perhaps susceptibility) to the development of IBD. However, the triggering factor for activation of the body's immune system has yet to be identified. Factors that can turn on the body's immune system include an infectious agent (as yet unidentified), an immune response to an antigen (e.g., protein from cow milk), or an autoimmune process. As the intestines are always exposed to things that can cause immune reactions, more recent hypothesis is that there is a failure of the organism to turn off normal immune responses.
IBD is a chronic disease, and affected subjects go through periods in which the disease flares up and causes symptoms, followed by periods of remission, in which symptoms disappear or decrease and good health returns.
Symptoms may range from mild to severe and generally depend upon the part of the intestinal tract involved. They include the following: abdominal cramps and pain; bloody diarrhea; severe urgency to have a bowel movement; fever; loss of appetite; weight loss; anemia (due to blood loss).
Intestinal complications of inflammatory bowel disease include the following: profuse bleeding from the ulcers; perforation (rupture) of the bowel; strictures and obstruction (in persons with Crohn's disease, strictures often are inflammatory and frequently resolve with medical treatment); fixed or fibrotic (scarring) strictures may require endoscopic or surgical intervention to relieve the obstruction. In ulcerative colitis, colonic strictures should be presumed to be malignant (cancerous). Fistulae (abnormal passage) and perianal disease are more common in persons with Crohn's disease. Toxic megacolon (acute nonobstructive dilation of the colon) is a life-threatening complication of ulcerative colitis and requires urgent surgical intervention. The risk of colon cancer in ulcerative colitis begins to rise significantly above that of the general population after approximately 8-10 years of diagnosis. The risk of cancer in Crohn's disease may equal that of ulcerative colitis if the entire colon is involved. The risk of small intestine malignancy is increased in Crohn's disease.
Extraintestinal involvement of IBD refers to complications involving organs other than the intestines. These affect only a small percentage of people with IBD. Persons with IBD may have arthritis, skin conditions, inflammation of the eye, liver and kidney disorders, and bone loss.
Diagnosis of IBD is currently done mainly through a combination of exams and tests, which include: stool examination, fecal occult blood test, complete blood count, electrolyte panel, LFTs (measure alanine transaminase, aspartate transaminase, alkaline phosphatase, albumin, total protein, and bilirubin levels).
Radiology (abdomen X-ray or barium enema, e.g.) and endoscopic procedures (colonoscopy and sigmoidoscopy, e.g.) are also used for the diagnosis of IBD. Clearly, there is still no clear cut diagnostic method for IBD, and there is a need for molecular markers which may serve for differential and specific diagnosis of IBD.
Non-limiting examples of types of cancer include adrenocortical cancer; Malignant melanoma; Non-melanoma skin cancer; Cutaneous T-cell Lymphoma; Kaposi's Sarcoma; Bladder cancer; Colon cancer; Colorectal cancer; Rectal cancer; Neuroectodermal and Pineal cancer; Childhood Brain Stem Glioma; Childhood Cerebellar Astrocytoma; Childhood Cerebral Astrocytoma; Childhood medulloblastoma; Childhood visual pathway Glioma; Meningioma; Mixed Glioma; Oligodendroglioma; Astrocytoma; Ependymoma; Pituitary adenoma; Metastasic Adenocarcinoma; Acoustic neuroma; Paravertebral Malignant teratoma; Breast cancer; Ductal carcinoma; Mammary gland neoplasia; Ovarian cancer; Carcinoid tumour; Cervical cancer; Uterus cancer; Endometrial cancer; Vaginal cancer vulva cancer Gestational Trophoblastic cancer; Fallopian cancer; Uterine sarcoma; Leukemia; Lymphoma (Hodgkin's disease and Non Hodgkin's disease); Neuroblastoma; Retinoblastoma; Soft tissue Sarcomas; Wilm's tumour; Fanconi Anemia; Langerhan's Cells Histiocytosis; Malignant Rhabdoid Tumour of Kidney; Liver cancer; Neuroblastoma; Retinoblastoma; Choriocarcinoma; Endocrine cancers; Endometrial cancer; Esophageal cancer; Ewing's Sarcoma; Eye cancer; Gastric cancer; Gastrointestinal cancers; Genitourinary cancers; Glioma; Gynecological cancers; Head and neck cancer; Hepatocellular cancer; Hypopharynx cancer; Islet call cancer; Kidney cancer; Laryngeal cancer; Lung cancer; Lymphoma; Male breast cancer; Melanoma; Mesothelioma; Myeloma, multiple; Nasopharyngeal cancer; Non-melanoma Skin cancer; Esophageal cancer; Osteosarcoma; Ovarian cancer; Pancreas cancer; Pituitary cancer; Prostate cancer; Renal cell carcinoma; Retinoblastoma; Rhabdomyosarcoma; Sarcoma; Skin cancer; Squamous cell carcinoma; Stomach cancer; Testicular cancerthymus cancer; Thyroid cancer; Transitional cells cancer; Trophoblastic cancer; Uterus cancer; Acute Lymphatic leukemia; Acute myeloid leukemia; Adenocystic carcinoma; Anal cancer; Bone cancer; Bowel cancer; Ductal carcinoma; Liposarcoma; Neuroblastoma; Nephroblastoma and Osteosarcoma.
Inflammatory diseases include sepsis, endotoxemia, pancreatitis, uveitis, hepatitis, peritonitis, keratitis, SIRS and injury-induced inflammation.
Diseases linked to fertility include male infertility and female infertility. Male infertility can be caused by a variety of problems. Some of the more common disorders are listed below:                Deficient Sperm Production: Ninety percent of male infertility is caused by the failure to produce enough sperm. Azzospermia occurs when no sperm is produced while oligospermia is diagnosed when few sperm are produced;        Varicocele;        Other Disorders: Other disorders that can cause male infertility include abnormal development or damage of the testes (caused by endocrine disorders or inflammation), disorders of accessory glands, coital disorders, exposure to diethylstilbestrol (DES) a synthetic estrogen used in the 1950's and 1960's that caused cysts in the male reproductive tract, undescended testicles, and in rare cases genetic disorders such as a chromosomal abnormality.        
Female infertility can also be caused by a variety of problems. Some of the more common disorders are Polycystic Ovarian Disease, Pelvic Inflammatory Disease, Ovulatory Dysfunction, Uterine Fibroids, Endometriosis, and Immunological Infertility.
Disorders of carbohydrate metabolism occur in many forms. The most common disorders are acquired. Acquired or secondary derangements in carbohydrate metabolism, such as diabetic ketoacidosis, hyperosmolar coma, and hypoglycemia, all affect the central nervous system. Many forms and variants of peripheral nerve disease also are seen in diabetes. The remaining disorders of carbohydrate metabolism are the rare inborn errors of metabolism (i.e. genetic defects).
The acquired disorders of carbohydrate metabolism are fairly common, both in the United States and internationally. Hypoglycemia is a common cause of neurological disease, especially acute mental deterioration, memory loss, disorientation, obtundation, and coma, among both alcoholics and patients with diabetes who are treated with insulin. Hyperinsulinemia from other causes is rare, but pancreatic tumors could be the cause. Diabetes, with its various neurological complications, is among the most common disorders treated in adult patients.
The inherited disorders of carbohydrate metabolism are rare. Severe defects of the pyruvate dehydrogenase (PDH) complex and the benign chemical anomaly called pentosuria have been reported in very few (2-6) patients.
Hypoglycemia, diabetic ketoacidosis, and hyperosmolar coma are all potentially fatal but potentially curable conditions.
In WO 2009/083968 the present inventors described a protein, denominated KTPAF50, which was shown to be specifically expressed in the placenta, kidney (adult and fetal), pancreas and testis, while in the hematopoietic tissue this protein was detected in resting and activated CD8+ cells, resting and activated mononuclear cells, as well as in resting and activated CD19+ cells.
Surprisingly, upon developing specific antibodies to KTPAF50, the inventors show, in the present invention, that expression of KTPAF50 may be correlated with specific disease states, particularly in cancer and autoimmune disorders.
Even more unexpectedly, the present inventors show that KTPAF50-specific antibodies are potent regulators of cell growth and cytokine expression.
Therefore, it is an object of the present invention to provide antibodies which specifically recognize KTPAF50, as well as their uses in diagnosis and treatment of cancer, autoimmune disorders, graft rejection, neurodegenerative diseases and diabetes.
As will be shown by the specification and the following Examples, the diagnostic method of the invention is particularly suitable for detection and monitoring of certain types of cancer and autoimmune disorders.
These and other uses and objects of the invention will become apparent as the description proceeds.